Kidney Urate Underexcretion Mediates the Relationship between Per- and Polyfluoroalkyl Substances and their Alternatives and Uric Acid Levels: Evidence from a Case–Control Study and an Animal Study

Numerous studies have indicated a relationship between per- and polyfluoroalkyl substances (PFASs) with uric acid levels; yet, the underlying mechanism remains unclear. To investigate this, we conducted a case-control study with 990 adults and animal experiments to examine the impact on kidney urate underexcretion. An interquartile range increase in PFASs was negatively associated with the fractional excretion of uric acid (FEUA%), an index for evaluating kidney urate excretion. Specifically, the association for 6:2 Cl-PFESA was β = -0.18 (95% CI -0.35, -0.02). Additionally, changes in FEUA (%) was negatively associated with uric acid levels (β = -13.42, 95% CI: -15.74, -11.09). Mediation analysis revealed that FEUA (%) mediated 14.22-25.63% of the association between PFASs and the uric acid level. Weighted Quantile Sum (WQS) models show that 6:2 Cl-PFESA had the greatest impact on FEUA (%) (weight: 0.585). Animal studies demonstrated a significant decrease in FEUA (%) and changes in uric acid transporters. In the 400 μg/L CI-PFESA exposure group, FEUA (%) decreased by 0.22-fold, while ABCG2 and NPT4 protein levels decreased by 0.622-fold and 0.729-fold, respectively; the levels of OAT10 increased by 1.331-fold compared with controls. Network toxicology and molecular biology analyses suggested that these effects may be mediated through the activation of the TLR4/NF-κB/NLRP3 axis.